6,5-Fused bicyclic heterocycles

ABSTRACT

The present invention provides compounds of Formula (I) wherein Q 1 , Q 2 , Q 3 , Q 4 , Y 1 , Y 2 , and Z are as defined in the description, and pharmaceutically acceptable salts thereof, and C 1 -C 8  alkyl esters thereof, which are useful for the treatment of diseases responsive to the inhibition of the enzyme 15-lipoxygenase. Thus, the compounds of Formula (I) and their pharmaceuticalyl acceptable salts are useful for treating diseases with an inflammatory component, including atherosclerosis, diseases involving chemotaxis of monocytes, inflammation, stroke, coronary artery disease, asthma, arthritis, colorectal cancer, and psoriasis.

This application claims the benefit of PCT/US01/15112 filed Sep. 5,2001, which claims the benefit of U.S. Provisional Application60/211,761 filed Jun. 14, 2000; the entire contents of each of which arehereby incorporated herein by reference.

FIELD OF THE INVENTION

The invention provides 6,5-fused bicyclic compounds, pharmaceuticalcompositions thereof, and methods of making and using such compounds andcompositions to inhibit the 15-lipoxygenase enzyme, and thus treatdiseases with an inflammatory component

BACKGROUND OF THE INVENTION

Hypercholesterolemia can induce monocytes to migrate into the arterialwall and mature into foam cells or tissue macrophages that accumulatefatty material, including cholesterol esters. For example, continuedcreation of foam cells thickens the inner lining of medium and largearteries, thereby forming atherosclerotic plaques or lesions containingcholesterol, smooth muscle cells, and connective tissue cells. Affectedarteries lose elasticity and become narrowed or obstructed by theplaques. These events are the hallmark of the disease atherosclerosis.Furthermore, atherosclerotic plaques may collect calcium, becomebrittle, and even rupture, triggering the formation of a blood clot orthrombus capable of occluding an artery and causing a stroke or a heartattack. In addition to atherosclerosis, hypercholesterolemia plays arole in peripheral vascular diseases of small arteries, veins, andlymphatics. Thus, hypercholesterolemia may also affect the arms, legs,kidneys, and other vital organs in addition to the heart and brain.

Cholesterol is transported in blood in particles called lipoproteins,such as low-density lipoproteins. Low-density lipoproteins also containpolyunsaturated fatty acids and are necessary for foam cell formation.

Lipoxygenases are enzymes that catalyze the oxidation of polyunsaturatedfatty acids and esters thereof, including those found in low-densitylipoproteins. For example, the enzyme 15-lipoxygenase (15-LO) oxidizesesterified polyenoic fatty acids. 15-LO has been implicated ininflammatory disorders and in the origin and recruitment of foam cells.In addition to modifying lipoproteins involved in the formation of foamcells, 15-LO also mediates an inflammatory reaction in theatherosclerotic lesion. In human monocytes, 15-LO is induced by thecytokine IL-4.

Inhibitors of 15-LO are therefore useful to prevent and treat diseaseswith an inflammatory component such as asthma, psoriasis,osteoarthritis, rheumatoid arthritis, colorectal cancer, andatherosclerosis. For example, it has been shown that treatment with aninhibitor of 15-LO suppressed atherogenesis, or the production ofatheroma, a fatty degeneration of the arterial wall, in rabbits fed ahigh-fat diet.

An object of this invention is to provide new 6,5-fused heterocyclesthat are potent inhibitors of 15-LO, and are thus useful for thetreatment of diseases and disorders containing an inflammatorycomponent.

SUMMARY OF THE INVENTION

The invention provides a compound of Formula I:

wherein:

-   Q₁, Q₂, Q₃, and Q₄ are independently selected from CX and N, wherein    1 or 2 of Q₁, Q₂, Q₃, and Q₄ are N; or each of Q₁, Q₂, Q₃, and Q₄ is    CH₂ and there is a C—C double bond between the carbon atoms bearing    Q₁ and Y₁, and Q₄ and Z, respectively, wherein-   X is independently selected from H, halo, hydroxy, CF₃, R₁, OR₁,    CO₂R₁, NO₂, NH₂, and SR₁, wherein R₁ is H or C₁-C₄ alkyl;    is absent or a double-bond optionally between Y₁ and Y₂ when Y₁ and    Y₂ are independently CH or N or between Y₂ and Z when Y₂ is CH or N    and Z is CH;-   one of Y₁ and Y₂ is CH, N, NH, S, or O; and the other one of Y₁ and    Y₂ is C—W—Ar, wherein W is absent (in other words, a covalent bond),    O, S, NR₂, SO, SO₂, CO, CHOH, CH₂, NR₂CH₂, CH₂NR₂, NR₂(CO), or    (CO)NR₂, wherein R₂ is H or C₁-C₄ alkyl,-   Ar is a phenyl substituted at the 3- and 4-positions relative to W,    with R₃ and R₄, respectively, wherein-   R₃ is selected from H, NHR_(a), halo, C₁-C₄ haloalkyl, COOH,    —COO(C₁-C₆ alkyl), (phenyl)C₁-C₆ alkoxy, hydroxy, C₁-C₆ alkoxy,    —NH(CO)(C₁-C₆ alkyl), nitro, and C₁-C₆ aminoalkyl, wherein R_(a) is    H, C₁-C₄ alkyl, C₃-C₈ cycloalkyl, phenyl, C₂-C₆ heteroaryl, benzyl,    CH₂—(C₂-C₆ heterocyclic radical), or -M-T, wherein M is sulfonyl,    SO₂NR_(b), CONR_(b), CSNR_(b), or CSR_(b), wherein R_(b) is H, C₁-C₄    alkyl, or C₂-C₆ heterocyclic radical, and T is C₁-C₁₈ alkyl, phenyl,    or C₃-C₆ heterocyclic radical, and-   R₄ is C₁-C₂ alkoxy, C₁-C₂ thioalkoxy, hydroxy, halo, or C₁-C₄ alkyl;-   Z is NR₅, S, O, C, or CH, wherein R₅ is H, [phenyl(C₁-C₄    alkyl)oxycarbonyl, (C₁-C₄ alkyl)oxycarbonyl, (C₃-C₈    cycloalkyl)oxycarbonyl, (C₃-C₈ cycloalkyl)-(C₁-C₄ alkyl)oxycarbonyl,    or (C₆-C₁₀ aryl)oxycarbonyl;-   wherein each hydrocarbyl or heterocyclic radical above is optionally    substituted with between 1 and 3 substituents independently selected    from halo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkenyl, C₁-C₄    alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, N-acetyl,    O-acetyl, C₁-C₄ thioalkyl, C₁-C₄ alkoxy, COOR₆, wherein R₆ is H or    C₁-C₆ alkyl, SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂, acetyl, di(C₁-C₄    alkyl)amino, and nitro, wherein each substituent alkyl, cycloalkyl,    alkenyl, alkynyl, or phenyl is in turn optionally substituted with    between 1 and 3 substituents independently selected from halo, C₁-C₂    alkyl, hydroxyl, amino, and nitro;    and pharmaceutically acceptable salts thereof; and C₁-C₈ alkyl    esters thereof.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, and C₁-C₈ alkyl esters thereof, wherein Q₄ is N.

More preferred are compounds of Formula II

-   wherein X, R₃, R₄, and R₅ are as defined above, and pharmaceutically    acceptable salts thereof, and C₁-C₈ alkyl esters thereof.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein Q₃ isN.

More preferred are compounds of Formula III

-   wherein X, R₃, R₄, and R₅ are as defined above, and pharmaceutically    acceptable salts thereof, and C₁-C₈ alkyl esters thereof.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein Q₂ isN.

More preferred are compounds of Formula IV

-   wherein X, R₃, R₄, and R₅ are as defined above, and pharmaceutically    acceptable salts thereof, and C₁-C₈ alkyl esters thereof.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein Q₁ isN.

More preferred are compounds of Formula V

-   wherein X, R₃, R₄, and R₅ are as defined above, and pharmaceutically    acceptable salts thereof, and C₁-C₈ alkyl esters thereof.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein Q₁ andQ₄ are N.

More preferred are compounds of Formula VI

-   wherein X, R₃, R₄, and R₅ are as defined above, and pharmaceutically    acceptable salts thereof, and C₁-C₈ alkyl esters thereof.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein Q₂ andQ₄ are N.

More preferred are compounds of Formula VII

-   wherein X, R₃, R₄, and R₅ are as defined above, and pharmaceutically    acceptable salts thereof, and C₁-C₈ alkyl esters thereof.

Also preferred are compounds of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein eachof Q₁, Q₂, Q₃, and Q₄ is CH₂.

More preferred are compounds of Formula VIII

-   wherein R₃, R₄, and R₅ are as defined above, and pharmaceutically    acceptable salts thereof, and C₁-C₈ alkyl esters thereof.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein Q₃ andQ₄ are N.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein Q₁ andQ₂ are N.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein Q₂ andQ₃ are N.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein Q₁ andQ₃ are N.

Also preferred are compounds of Formula IX

-   wherein Q₁, Q₂, Q₃, Q₄, R₃, R₄, and R₅ are as defined above, and    pharmaceutically acceptable salts thereof, and C₁-C₈ alkyl esters    thereof.

In another preferred embodiment, the invention provides a compound ofFormula (A):

and pharmaceutically acceptable salts thereof, and C₁-C₈ alkyl estersthereof,

wherein:

-   Q₁, Q₂, Q₃, and Q₄ are independently selected from CX and N, wherein    1 or 2 of Q₁, Q₂, Q₃, and Q₄ are N or each of Q₁, Q₂, Q₃, and Q₄ is    CH₂ and there is a C—C double bond between the carbon atoms bearing    Q₁ and N, and Q₄ and N, respectively, wherein,-   X is independently selected from H, halo, hydroxy, CF₃, R₁, OR₁,    CO₂R₁, NO₂, NH₂, and SR₁, wherein R₁ is H or C₁-C₄ alkyl;-   R_(a) is H, C₁-C₄ alkyl, C₃-C₈ cycloalkyl, phenyl, C₂-C₆ heteroaryl,    benzyl, CH₂—(C₂-C₆ heterocyclic radical), C(O)NH₂, or -M-T, wherein    M is sulfonyl, SO₂NR_(b), CONR_(b), CSNR_(b), or CSR_(b), wherein    R_(b) is H, C₁-C₄ alkyl, or C₂-C₆ heterocyclic radical, and T is    C₁-C₁₈ alkyl, phenyl, or C₂-C₆ heterocyclic radical;-   R₄ is C₁-C₂ alkoxy, C₁-C₂ thioalkoxy, hydroxy, halo, or C₁-C₄ alkyl;-   R₅ is H, (phenyl)(C₁-C₄ alkyl)oxycarbonyl, (C₁-C₄ alkyl)oxycarbonyl,    (C₃-C₈ cycloalkyl)oxycarbonyl, (C₃-C₈ cycloalkyl), (C₁-C₄    alkyl)oxycarbonyl, or (C₆-C₁₀ aryl)oxycarbonyl;-   wherein each hydrocarbyl or heterocyclic radical above is optionally    substituted with between 1 and 3 substituents independently selected    from halo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkenyl, C₁-C₄    alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, N-acetyl,    O-acetyl, C₁-C₄ thioalkyl, C₁-C₄ alkoxy, COOR₆, wherein R₆ is H or    C₁-C₆ alkyl, SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂, acetyl, di(C₁-C₄    alkyl)amino, and nitro, wherein each substituent alkyl, cycloalkyl,    alkenyl, alkynyl, or phenyl is in turn optionally substituted with    between 1 and 3 substituents independently selected from halo, C₁-C₂    alkyl, hydroxyl, amino, and nitro.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein R_(a)or R_(b) is a heterocyclic radical selected from 3-pyridyl, 3-picolinyl,2-thienyl, 3-thienyl, dansyl, 8-quinoyl, and imidazolyl.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein R_(a)or R_(b) is one of said phenyl, benzyl, alkyl, heterocyclic radical, orcycloalkyl groups substituted with at least one substituent selectedfrom halo, hydroxyl, amino, (amino)sulfonyl, N-acetyl, O-acetyl, C₁-C₄thioalkyl, C₁-C₄ alkoxy, COOR₆, SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂,acetyl, di(C₁-C₄ alkyl)amino, trifluoromethyl, and nitro, and wherein Wis a covalent bond.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein saidsubstituent is CO₂R₆, N-acetyl, di(C₁-C₄ alkyl)amino, hydroxy, halo, ortrifluoromethyl.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, and C₁-C₈ alkyl esters thereof, wherein R_(a) is a phenylor benzyl having a substituent in the 3- or 4-position, substituents inthe 3- and 5-positions, or substituents in the 3- and 4-positions.

Also preferred is a compound of Formula I, and pharmaceuticallyacceptable salts thereof, and C₁-C₈ alkyl esters thereof, wherein R_(a)is C₁-C₄ alkylsulfonyl or C₁₀-C₁₄ alkylsulfonyl.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, and C₁-C₈ alkyl esters thereof, wherein R₄ is methoxy,hydroxy, or thiomethoxy.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, and C₁-C₈ alkyl esters thereof, wherein R₄ is methoxy.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, and C₁-C₈ alkyl esters thereof, wherein R₅ is H.

Still more preferred is a compound selected from the group consistingof:

-   1-(3,5-Dichloro-phenyl)-3-[5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenyl]-thiourea;-   [5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenyl]-urea;-   5-(3H-Imidazo[4,5-c]pyridin-2-yl)-2-methoxy-phenylamine;-   5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenylamine (Chemical    Example 1);-   1-(3,5-Dichloro-phenyl)-3-[5-(3H-imidazo[4,5-c]pyridin-2-yl)-2-methoxy-phenyl]-thiourea;-   [5-(3H-Imidazo[4,5-c]pyridin-2-yl)-2-methoxy-phenyl]-urea;-   Thiophene-2-sulfonic acid    [5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenyl]-amide (Chemical    Example 2);-   Thiophene-2-sulfonic acid    [5-(3H-imidazo[4,5-c]pyridin-2-yl)-2-methoxy-phenyl]-amide;-   2-Methoxy-5-(9H-purin-8-yl)-phenylamine;-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(9H-purin-8-yl)-phenyl]-thiourea;-   [2-Methoxy-5-(9H-purin-8-yl)-phenyl]-urea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(9H-purin-8-yl)-phenyl]-amide;-   5-(7H-Imidazo[4,5-c]pyridazin-6-yl)-2-methoxy-phenylamine;-   1-(3,5-Dichloro-phenyl)-3-[5-(7H-imidazo[4,5-c]pyridazin-6-yl)-2-methoxy-phenyl]-thiourea;-   [5-(7H-Imidazo[4,5-c]pyridazin-6-yl)-2-methoxy-phenyl]-urea;-   Thiophene-2-sulfonic acid    [5-(7H-imidazo[4,5-c]pyridazin-6-yl)-2-methoxy-phenyl]-amide;-   5-(1H-Imidazo[4,5-d]pyridazin-2-yl)-2-methoxy-phenylamine;-   1-(3,5-Dichloro-phenyl)-3-[5-(1H-imidazo[4,5-d]pyridazin-2-yl)-2-methoxy-phenyl]3-thiourea;-   [5-(1H-Imidazo[4,5-d]pyridazin-2-yl)-2-methoxy-phenyl]-urea;-   Thiophene-2-sulfonic acid    [5-(1H-imidazo[4,5-d]pyridazin-2-yl)-2-methoxy-phenyl]-amide;-   5-(1H-Imidazo[4,5-b]pyrazin-2-yl)-2-methoxy-phenylamine;-   1-(3,5-Dichloro-phenyl)-3-[5-(1H-imidazo[4,5-b]pyrazin-2-yl)-2-methoxy-phenyl]-thiourea;-   [5-(1H-Imidazo[4,5-b]pyrazin-2-yl)-2-methoxy-phenyl]-urea; and-   Thiophene-2-sulfonic acid    [5-(1H-imidazo[4,5-b]pyrazin-2-yl)-2-methoxy-phenyl]-amide.

Also still more preferred is a compound selected from the groupconsisting of:

-   Thiophene-2-sulfonic acid    [2-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;-   3-{[2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenylamino]-methyl}-phenol;-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-thiourea;-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;-   3-{[2-Methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenylamino]-methyl}-phenol;-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;-   3-{[2-Methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenylamino]-methyl}-phenol;-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenylamino]-methyl}-phenol.

Also still more preferred is a compound selected from the groupconsisting of:

-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]-amide;-   [2-Methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;-   3-{[2-Methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenylamino]-methyl}-phenol;-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(7H-pyrrolo[2,3-c]pyridazin-6-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(7H-pyrrolo[2,3-c]pyridazin-6-yl)-phenyl]-amide;-   [2-Methoxy-5-(7H-pyrrolo[2,3-c]pyridazin-6-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(7H-pyrrolo[2,3-c]pyridazin-6-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;-   3-{[2-Methoxy-5-(7H-pyrrolo[2,3-c]pyridazin-6-yl)-phenylamino]-methyl}-phenol;-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(5H-pyrrolo[3,2-c]pyridazin-6-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(5H-pyrrolo[3,2-c]pyridazin-6-yl)-phenyl]-amide;-   [2-Methoxy-5-(5H-pyrrolo[3,2-c]pyridazin-6-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(5H-pyrrolo[3,2-c]pyridazin-6-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;-   3-{[2-Methoxy-5-(5H-pyrrolo[3,2-c]pyridazin-6-yl)-phenylamino]-methyl}-phenol;-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[2,3-d]pyridazin-2-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(1H-pyrrolo[2,3-d]pyridazin-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(1H-pyrrolo[2,3-d]pyridazin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(1H-pyrrolo[2,3-d]pyridazin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;-   3-{[2-Methoxy-5-(1H-pyrrolo[2,3-d]pyridazin-2-yl)-phenylamino]-methyl}-phenol;-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-amide;-   [2-Methoxy-5-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;-   3-{[2-Methoxy-5-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenylamino]-methyl}-phenol;-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-6-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-6-yl)-phenyl]-amide;-   [2-Methoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-6-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-6-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-6-yl)-phenylamino]-methyl}-phenol.

Also still more preferred is a compound of Formula I selected from thegroup consisting of:

-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(4,5,6,7-tetrahydro-1H-indol-2-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(4,5,6,7-tetrahydro-1H-indol-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(4,5,6,7-tetrahydro-1H-indol-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(4,5,6,7-tetrahydro-1H-indol-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(4,5,6,7-tetrahydro-1H-indol-2-yl)-phenylamino]-methyl}-phenol.

The invention also provides pharmaceutical compositions comprisingcompounds of Formula I, together with a pharmaceutically acceptablecarrier, diluent, or excipient. Preferred compositions comprise acompound of Formulas II through IX or (A) with a pharmaceuticallyacceptable carrier, diluent, or excipient.

The invention also provides methods for treating mammals with diseasesrelating to the 15-LO cascade. These methods are for treating,preventing, or ameliorating the related condition or disease. Thesemethods include the following.

A method for inhibiting 15-LO, said method comprising administering to apatient in need of 15-lipoxygenase inhibition apharmaceutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, or C₁-C₈ alkyl esters thereof.

A method for treating or preventing atherosclerosis, said methodcomprising administering to a patient at risk or in need of suchtreatment a therapeutically-effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof, or C₁-C₈ alkyl estersthereof.

A method for inhibiting the chemotaxis of monocytes, said methodcomprising administering to a patient in need of inhibition of monocyticmigration a therapeutically-effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof, or C₁-C₈ alkyl estersthereof.

A method for treating or preventing inflammation, said method comprisingadministering to patient at risk or in need of such treatment atherapeutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, or C₁-C₈ alkyl esters thereof.

A method for treating or preventing stroke, said method comprisingadministering to a patient at risk or in need of such treatment atherapeutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, or C₁-C₈ alkyl esters thereof.

A method for treating or preventing coronary artery disease, said methodcomprising administering to a patient at risk or in need of suchtreatment a therapeutically-effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof, or C₁-C₈ alkyl estersthereof.

A method for treating or preventing asthma, said method comprisingadministering to patient at risk or in need of such treatment atherapeutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, or C₁-C₈ alkyl esters thereof.

A method for treating or preventing arthritis, said method comprisingadministering to patient at risk or in need of such treatment atherapeutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, or C₁-C₈ alkyl esters thereof.

A method for treating or preventing colorectal cancer, said methodcomprising administering to a patient at risk or in need of suchtreatment a therapeutically-effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof, or C₁-C₈ alkyl estersthereof.

A method for treating or preventing psoriasis, said method comprisingadministering to a patient at risk or in need of such treatment atherapeutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof, or C₁-C₈ alkyl esters thereof.

Other aspects and features of the invention will be apparent from thedisclosure, examples, and claims set forth below.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides compounds of Formula I and methods of making andusing them. Other features of the invention, and preferred embodimentsthereof, will become apparent from the examples and claims below.

A. Terms

Certain terms used herein are defined below and by their usagethroughout this disclosure.

Alkyl groups include aliphatic (i.e., hydrocarbon radicals containinghydrogen and carbon atoms) with a free valence. Alkyl groups areunderstood to include straight chain and branched structures. Preferredalkyl groups have from 1 to 6 carbon atoms. Examples of typical alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, n-butyl,isobutyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl,2,3-dimethyl hexyl, 1,1-dimethylpentyl, heptyl, and octyl. Cycloalkylgroups are C₃-C₈ cyclic structures, examples of which includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.

Alkyl and cycloalkyl groups can be substituted with 1, 2, 3 or moresubstituents which are independently selected from halo (fluoro, chloro,bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino,cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical,(heterocyclic radical)oxy, (amino)sulfonyl, N-acetyl, O-acetyl, C₁-C₄thioalkyl, C₁-C₄ alkoxy, COOR₆, SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂,acetyl, trifluoromethyl, and nitro. Specific examples include COOH,thiomethyl, methoxy, ethoxy, dimethylamino, ethylmethylamino,diethylamino, and chloro. Other examples include fluoromethyl,hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl)methyl,cyclopropylmethyl, methylcyclopropyl, benzyloxyethyl,(3-pyridinyl)methyl, (2- or 3-furanyl)methyl, (2-thienyl)ethyl,hydroxypropyl, aminocyclohexyl, 2-dimethyl-aminobutyl, methoxymethyl,2-ethoxycyclopentyl, N-pyridinylethyl, diethylaminoethyl andcyclobutylmethyl.

Alkenyl groups are analogous to alkyl groups, but have at least onedouble-bond (two adjacent sp² carbon atoms). Depending on the placementof a double-bond and substituents, if any, the geometry of thedouble-bond may be entgegen (E), zusammen (Z), cis, or trans. Similarly,alkynyl groups have at least one triple-bond (two adjacent sp carbonatoms). Unsaturated alkenyl or alkynyl groups may have one or moredouble- or triple-bonds, respectively, or a mixture thereof; like alkylgroups, they may be straight chain or branched, and they may besubstituted as described above and throughout the disclosure. Examplesof alkenyls, alkynyls, and substituted forms include cis-2-butenyl,trans-2-butenyl, 3-butynyl, 3-phenyl-2-propynyl,3-(2′-fluorophenyl)-2-propynyl, 3-methyl(5-phenyl)-4-pentynyl,2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2-propenyl,4-hydroxy-3-butynyl, 3-(3-fluorophenyl)-2-propynyl, and2-methyl-2-propenyl.

The foregoing groups are referred to collectively as “hydrocarbyl”groups. More general forms of substituted hydrocarbyls includehydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl,hydroxyaryl, and corresponding forms for the prefixes amino-, halo-(e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-,cycloalkyl- and so on, or combinations of substituents. According toFormula I, therefore, substituted alkyls include hydroxyalkyl,aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such asmethylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl,dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl,(heterocyclic radical)alkyl, and (heterocyclic radical)oxyalkyl and soon. Where R_(a) or R_(b) are both phenyl, for example, R_(a) thusincludes 3-halo-4-hydroxyphenyl, 3-(fluoro or chloro)-4-nitrophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,3-hydroxy-4-nitrophenyl, 4-hydroxy-3-nitrophenyl, 3-chlorophenyl,4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-aminophenyl,4-aminophenyl, 3,5-diethylphenyl, 3-methylphenyl, 4-methylphenyl,3-nitrophenyl, 4-nitrophenyl, 3-nitro-4-chlorophenyl, 3-cyanophenyl,4-cyanophenyl, 3-methyleneaminophenyl, 4-methyleneaminophenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl,4-chloro-3-trifluoromethylphenyl, 3-carbomethoxyphenyl,4-carbomethoxyphenyl, bis(3,5-trifluoromethyl)phenyl, 4-t-butylphenyl,4-n-butylphenyl, 4-isopropylphenyl; 3-acetylphenyl, 4-sulfonic acid(e.g., sodium salt), 3-carboxyphenyl, 4-carboxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-acetamidophenyl,3-amino-4-halophenyl, 3-alkoxy-4-halophenyl, 3-halo-4-alkylaminophenyl,4-(N,N-dimethylamino)phenyl, 3-cycloalkylphenyl,3(3′,5′-dihalophenyl)-4-nitrophenyl, 4-aryloxyphenyl,arylalkyloxyphenyl, heterocyclic radical phenyl, (heterocyclicradical)oxy, 4-sulfamoylphenyl (or 4-aminosulfonylphenyl),3-(alkylcarbonyloxy)phenyl such as 3-acetylphenyl, and 3-(C₁-C₄thioalkyl)phenyl.

Similarly, the invention features analogous examples of substitutedR_(a) on a heterocyclic radical. Heterocyclic radicals, which includebut are not limited to heteroaryls, include cyclic and bicyclic ringmoieties having between 1 and 4 heteroatoms selected independently fromO, S, and N, and having from 2 to 11 carbon atoms. The rings may bearomatic or nonaromatic, with sp² or sp³ carbon atoms. Examples include:furyl, oxazolyl, isoxazolyl, thienyl, thiophenyl, thiazolyl, pyrrolyl,imidazolyl, triazolyl such as 1,3,4-triazolyl, tetrazolyl, thiazolyl,oxazolyl, xanthenyl, pyronyl, pyridyl, pyrimidyl, triazinyl, pyrazinyl,pyridazinyl, indolyl, and pyrazolyl. Further examples of heterocyclicradicals include piperidyl, quinolyl, isothiazolyl, piperidinyl,morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl,pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, andoctahydrobenzofuranyl. Particularly preferred heterocyclic radicalsinclude 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-picolinyl, 2-thienyl,3-thienyl, 2-furyl, 3-furyl, dansyl, 8-quinoyl, 2-acetamido-4-thiazole,and imidazolyl. These may be substituted with one or more substituentssuch as halo, C₁-C₄ alkoxy, COOR₆, SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂,acetyl, trifluoromethyl. Examples of substituted heterocyclic radicalsinclude chloropyranyl, methylthienyl, fluoropyridyl,amino-1-,4-benzisoxazinyl, nitroisoquinolinyl, and hydroxyindolyl.Heterocyclic radicals can be bonded through a carbon atom or aheteroatom.

The term “patient” means a mammal such as a human or a domestic animalsuch as a dog, cat, horse, bovine, porcine, and sheep.

The term “effective amount” means that quantity of a compound of FormulaI that inhibits the 15-LO enzyme in a patient to an extent that resultsin prevention or treatment of an inflammatory condition or otherwisebenefits a patient by virtue of having endogenous 15-LO enzymesinhibited.

The term “halo” includes fluoro, chloro, bromo, and iodo.

The term “amino” means NH₂.

The terms “alkoxy” and “thioalkoxy” mean an alkyl group bonded throughan oxygen atom or a sulfur atom, respectively, wherein alkyl is definedabove unless limited in the number of carbons by a prefix to alkoxy orthioalkoxy such as, for example, C₁-C₂ or C₁-C₄.

B. Compounds

The invention compounds can be synthesized utilizing standard organicchemistry methodologies. Typical syntheses are shown in Schemes 1through 13 below, which are categorized according to “Type” for ease ofunderstanding.

Examples of compounds of the invention categorized by “Type” andreaction Scheme(s) used to prepare the compounds are shown below.

Type A (Schemes 3 and 4)

-   Thiophene-2-sulfonic acid    [2-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;-   3-{[2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenylamino]-methyl}-phenol;    and-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-thiourea.    Type B (Scheme 5)-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenylamino]-methyl}-phenol.    Type C (Scheme 6)-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenylamino]-methyl}-phenol.    Type D (Scheme 7)-   1-3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenylamino]-methyl}-phenol.    Type E (Scheme 8)-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazinyl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]-amide;-   [2-Methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenylamino]-methyl}-phenol.    Type F (Schemes 1 and 2)-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(7H-pyrrolo[2,3-c]pyridazin-6-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(7H-pyrrolo[2,3-c]pyridazin-6-yl)-phenyl]-amide;-   [2-Methoxy-5-(7H-pyrrolo[2,3-c]pyridazin-6-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(7H-pyrrolo[2,3-c]pyridazin-6-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(7H-pyrrolo[2,3-c]pyridazin-6-yl)-phenylamino]-methyl}-phenol.    Type G (Schemes 1 and 2)-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(5H-pyrrolo[3,2-c]pyridazin-6-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(5H-pyrrolo[3,2-c]pyridazin-6-yl)-phenyl]-amide;-   [2-Methoxy-5-(5H-pyrrolo[3,2-c]pyridazin-6-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(5H-pyrrolo[3,2-c]pyridazin-6-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(5H-pyrrolo[3,2-c]pyridazin-6-yl)-phenylamino]-methyl}-phenol.    Type H (Schemes 1 and 2)-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[2,3-d]pyridazin-2-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(1H-pyrrolo[2,3-d]pyridazin-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(1H-pyrrolo[2,3-d]pyridazin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(1H-pyrrolo[2,3-d]pyridazin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(1H-pyrrolo[2,3-d]pyridazin-2-yl)-phenylamino]-methyl}-phenol.    Type I (Scheme 9)-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-amide;-   [2-Methoxy-5-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenylamino]-methyl}-phenol.    Type J (Schemes 1 and 2)-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-6-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-6-yl)-phenyl]-amide;-   [2-Methoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-6-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-6-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-6-yl)-phenylamino]-methyl}-phenol.    Type K (Schemes 10 and 11)-   1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(4,5,6,7-tetrahydro-1H-indol-2-yl)-phenyl]-thiourea;-   Thiophene-2-sulfonic acid    [2-methoxy-5-(4,5,6,7-tetrahydro-1H-indol-2-yl)-phenyl]-amide;-   [2-Methoxy-5-(4,5,6,7-tetrahydro-1H-indol-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;-   [2-Methoxy-5-(4,5,6,7-tetrahydro-1H-indol-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;    and-   3-{[2-Methoxy-5-(4,5,6,7-tetrahydro-1H-indol-2-yl)-phenylamino]-methyl}-phenol.

The invention provides the disclosed compounds and closely related,pharmaceutically acceptable forms of the disclosed compounds, such assalts, esters, amides, hydrates or solvated forms thereof; masked orprotected forms; and racemic mixtures, or enantiomerically or opticallypure forms (at least 90%, and preferably 95%, 98% or greater purity).

Pharmaceutically acceptable salts, esters, and amides includecarboxylate salts (e.g., C₁-C₈ alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclic), amino acid addition salts, esters, and amides which arewithin a reasonable benefit/risk ratio, pharmacologically effective, andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. Representative salts includehydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,oxalate, valerate, oleate, palmitate, stearate, laurate, borate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactiobionate, and laurylsulfonate. These may include alkali metal andalkali earth cations such as sodium, potassium, calcium, and magnesium,as well as non-toxic ammonium, quaternary ammonium, and amine cationssuch as tetramethyl ammonium, methylamine, trimethylamine, andethylamine. See, for example, S. M. Berge, et al., “PharmaceuticalSalts,” J. Pharm. Sci., 1977;66:1-19 which is incorporated herein byreference. Representative pharmaceutically acceptable amides of theinvention include those derived from ammonia, primary C₁-C₆ alkyl aminesand secondary di(C₁-C₆ alkyl)amines. Secondary amines include 5- or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁-C₃ alkylprimary amines, and di(C₁-C₂ alkyl)amines. Representativepharmaceutically acceptable esters of the invention include C₁-C₆ alkyl,C₅-C₇ cycloalkyl, C₆-C₈ aryl, and C₆-C₈ aryl (C₁-C₆)alkyl esters.Preferred esters include methyl esters.

C. Synthesis

The invention compounds can be synthesized according to the followingthirteen schemes, or variants thereof.

Compounds of the present invention can be prepared using the generalsynthetic procedure shown in Scheme 1. The parent heterocycles can bepurchased or synthesized by methods known to those skilled in the art(A. R. Katritzky and C. W. Rees, “Comprehensive Heterocyclic Chemistry,The Structures, Reactions, Synthesis, and Uses of HeterocyclicCompounds,” Pergamon Press, NY, 1984;4(3.09):497-529). The free NH ofthe heterocycle is protected using the benzenesulfonyl group. Theheterocycle of formula (1) is treated with benzenesulfonyl chloride anda base such as potassium or sodium hydroxide in a solvent such asmethanol or ethanol to give the protected heterocycle of formula (2).The protected heterocycle of formula (2) is then deprotonated using abase such as n-BuLi in a solvent such as THF or diethyl ether, and theresulting organolithium species is then brominated with bromine to givea compound of formula (3). Lithium-halogen exchange with a base such asn-BuLi in a solvent such as THF or diethyl ether, followed by reactionwith triisopropyl borate at temperatures ranging from −20° C. to −78° C.converts the compound of formula (3) to the boronic acid of formula (4).Suzuki coupling of the compound of formula (4) with the aryl bromide offormula (5) in the presence of tetrakis(triphenylphosphine)palladium (0)as catalyst and a base such as aqueous potassium carbonate in a solventsuch as toluene gives the protected aryl heterocycle of formula (6).Reduction of the nitro group in the compound of formula (6) can beaccomplished with Raney nickel and hydrogen gas in a solvent such as THFor DMF to give the amino compound of formula (7). The compound offormula (7) can be deprotected using HBr in glacial acetic acid to givethe compound of formula (8). The compound of formula (8) can be reactedwith a variety of compounds such as for example, sulfonyl chlorides,isothiocyanates, aryl halides, and acylchlorides to yield a variety ofcompounds of the present invention such as for example, sulfonamides,thioureas, N-aryl analogs, and reductive amination products.

Alternatively, compounds of the present invention can be prepared asshown in Scheme 2. In Scheme 2, the bromo compound of formula (3) can betreated with hexamethylditin in a solvent such as benzene using acatalyst such as tetrakis(triphenylphosphine)palladium (0) at refluxtemperatures to give the trimethyltin compound of formula (9). Stillecoupling of the compound of formula (9) with the aryl bromide of formula(5) in the presence of tetrakis(triphenylphosphine) palladium (0) ascatalyst in a solvent such as benzene gives the compound of formula (6),which can be converted to compounds of the present invention asdescribed for Scheme 1.

In addition to the general methods of Schemes 1 and 2, which can beapplied to the synthesis of all target compounds, there are othermethods available for the synthesis of compounds of the presentinvention containing more specific ring systems. For the preparation ofcompounds of the present invention containing the1H-pyrrolo[2,3-b]pyridine ring system, the method of Houlihan W. J.,Parrino V. A., Uike Y., J. Org. Chem., 1981;46:4511-4515 can be employedas shown in Scheme 3. In Scheme 3, a key amide of formula (12) isprepared by reacting the acid of formula (10), which is commerciallyavailable, with oxalyl chloride in a solvent such as THF with a catalystsuch as DMF to give the corresponding acid chloride, which is thencoupled with 2-amino-3-methyl pyridine of formula (11) in a solvent suchas toluene using a base such as sodium or potassium carbonate at refluxtemperatures to give the amide of formula (12). Treatment of the amideof formula (12) with 2 or 3 equivalents of a base such as n-BuLi or IDAin a solvent such as THF or diethyl ether at temperatures ranging from−20° C. to +25° C. gives the aryl heterocycle of formula (13), which canbe converted to sulfonamides, thioureas, N-aryl analogs, and reductiveamination products according to the procedure described above for Scheme1 to provide compounds of the present invention containing the1H-pyrrolo[2,3-b]pyridine ring system.

In addition, compounds of the present invention containing the1H-pyrrolo[3,2-b]pyridine ring system can be prepared using the methodof Houlihan et al., by replacing 2-amino-3-methyl pyridine of formula(11) with 3-amino-2-methyl pyridine of formula (28) to give a compoundof formula (30) as shown in Scheme 7. A compound of formula (30) can beconverted to sulfonamides, thioureas, N-aryl analogs, and reductiveamination products according to the procedures described above forScheme 1 to also provide compounds of the present invention containingthe 1H-pyrrolo[3,2-b]pyridine ring system.

Alternatively, compounds of the present invention containing the1H-pyrrolo[2,3-b]pyridine ring system can be prepared utilizing themethod of Davis M. L., Wakefield B. J., Wardell J. A., Tetrahedron,1992;48:939-952 as shown in Scheme 4. In Scheme 4, deprotonation of3-methylpyridine of formula (15) with a base such as LDA in a solventsuch as THF or diethyl ether at temperatures ranging from −20° C. to 15°C., followed by reaction of the corresponding anion with thecommercially available benzonitrile of formula (14) gives anintermediate of formula (16), which on treatment with additional basecyclizes to give a compound of formula (13). The compound of formula(13) can be converted to sulfonamides, thioureas, N-aryl analogs, andreductive amination products according to the procedures described abovefor Scheme 1 to provide compounds of the present invention containingthe 1H-pyrrolo[2,3-b]pyridine ring system.

In addition, compounds of the present invention containing the1H-pyrrolo[2,3-b]pyrazine ring system can be prepared using the methodof Wakefield et al., by replacing 3-methylpyridine of formula (15) with2-methylpyrazine of formula (31) to give a compound of formula (33) asshown in Scheme 8. A compound of formula (33) can be converted tosulfonamides, thioureas, N-aryl analogs, and reductive aminationproducts according to the procedures described above for Scheme 1 toprovide compounds of the present invention containing the1H-pyrrolo[2,3-b]pyrazine ring system.

In addition, components of the present invention containing the7H-pyrrolo[2,3-d]pyrimidine ring system can also be prepared using themethod of Wakefield et al. by replacing 3-methylpyridine of formula (15)with 5-methylpyrimidine of formula (34) to give a compound of formula(36) as shown in Scheme 9. A compound of formula (36) can be convertedto sulfonamides, thioureas, N-aryl analogs, and reductive aminationproducts according to the procedures described above for Scheme 1 toprovide compounds of the present invention containing the7H-pyrrolo[2,3-d]pyrimidine ring system.

For preparation of compounds of the present invention containing the1H-pyrrolo[2,3-c]pyridine ring system, the method of Fisher M. H.,Schwartkopf G., Jr., Hoff D. R., J. Med. Chem., 1972;15:1168-1171 can beemployed as shown in Scheme 5. In Scheme 5, condensation of3-nitropicoline of formula (17) with the commercially available aldehydeof formula (18) in the presence of a base such as piperidine in asolvent such as methanol or ethanol gives the styrylpyridine of formula(19). The styrylpyridine of formula (19) can be reductively cyclizedusing triethyl phosphite in a solvent such as benzene at refluxtemperatures to yield a compound of formula (20). A compound of formula(20) can be converted to sulfonamides, thioureas, N-aryl analogs, andreductive amination products according to the procedures described abovefor Scheme 1 to provide compounds of the present invention containingthe 1H-pyrrolo[2,3-c]pyridine ring system.

For preparation of compounds of the present invention containing the1H-pyrrolo[3,2-c]pyridine ring system, another method of Fisher et al.,Supra., 1972 can be employed as shown in Scheme 6. In Scheme 6,treatment of 4-chloro-3-methyl pyridine of formula (21) with anoxidizing agent such as m-chloroperoxybenzoic acid in a solvent such asdichloromethane or 1,2-dichloroethane at temperatures ranging from −10°C. to 50° C. gives the corresponding N-oxide of formula (22). TheN-oxide of formula (22) is condensed with an aldehyde of formula (18) inthe same manner as described in Scheme 5 for the conversion of acompound of formula (18) to a compound of formula (19) to give compoundof formula (23). The compound of formula (23) is then reacted withhydrazine in a solvent such as methanol or ethanol to give the hydrazinoderivative of formula (24). Reaction of the hydrazino derivative offormula (24) with aqueous sodium nitrite in an acid such as dilute (10%)hydrochloric acid at ambient temperatures gives the azido compound offormula (25), which is thermally decomposed in a solvent such as tolueneat reflux temperatures to give the cyclized product formula (26).Reduction of the nitro group and deoxygenation of the pyridine-N-oxidein the cyclized product of formula (26) can be accomplished with Raneynickel and hydrogen gas in a solvent such as THF or DMF to give an aminocompound of formula (27). An amino compound of formula (27) can beconverted to sulfonamides, thioureas, N-aryl analogs, and reductiveamination products according to the procedures described above forScheme 1 to provide compounds of the present invention containing the1H-pyrrolo[3,2-c]pyridine ring system.

Compounds of the present invention containing the tetrahydroindole ringsystem can be prepared as shown in Schemes 10 and 11. In Scheme 10, themethod of Hippeli C., Zimmer R., Reissig H.-U., Liebigs Ann. Chem.,1990:469-474 was employed. In this method, treatment of the commerciallyavailable ketone of formula (36) with a brominating agent such asN-bromosuccinimide in a solvent such as chloroform or carbontetrachloride gives the bromo compound of formula (37). Treatment of thebromo compound of formula (37) with hydroxylamine in an aqueous methanolor ethanol solution gives the α-bromooxime of formula (38). Treatment ofthe α-bromooxime of formula (38) with the silyl enol ether of formula(39) and a base such as sodium carbonate in a solvent such as chloroformor dichloromethane at ambient temperatures gives the dihydro-1,2-oxazineof formula (40). Treatment of the dihydro-1,2-oxazine of formula (40)with molybdenum hexacarbonyl in acetonitrile at reflux temperaturesresults in deoxygenation and ring contraction to yield thetetrahydroindole of formula (41). The tetrahydroindole of formula (41)can be converted to sulfonamides, thioureas, N-aryl analogs, andreductive amination products according to the procedures described abovefor Scheme 1 to provide compounds of the present invention containingthe tetrahydroindole ring system.

Alternatively, compounds of the present invention containing thetetrahydroindole ring system can be prepared according to the method ofChiu P.-K, Sammes M. P., Tetrahedron, 1988;44:3531-3538 as shown inScheme 11. In Scheme 11, the requisite 1,4-diketone of formula (43) canbe prepared by a Stork alkylation of the enamine of formula (42) withthe bromo compound of formula (37) in a solvent such as dioxane atreflux temperatures. Paal-Knorr cyclization of the 1,4-diketone offormula (43) with liquid ammonia yields the desired compound of formula(41). The compound of formula (41) can be converted to sulfonamides,thioureas, N-aryl analogs, and reductive amination products according tothe procedures described above for Scheme 1 to provide compounds of thepresent invention containing the tetrahydroindole ring system.

Further compounds of the invention with a fused imidazole ring system,such as those of formula (A), can be made according to Scheme 12.Referring to Scheme 12, a diamino compound of formula (B) is condensedwith an activated carboxylic acid compound of formula (C), such as anacid halide or an imidazolide, to give the desired imidazo compound offormula (D). This condensation is a two-step process in which anintermediate amide is formed which then dehydrates to give the imidazocompound of formula (D). These two steps can be done in one pot byrefluxing with phosphorous oxychloride. The nitro group of the imidazocompound of formula (D) is reduced with an appropriate reagent such asRaney nickel with hydrogen gas or zinc in acetic acid to give theaniline compound of formula (E). The aniline compound of formula (E) canbe converted to a compound of formula (A), wherein Q₁, Q₂, Q₃, Q₄, R₄,R₅, and R_(a) are as defined above for the compound of formula (A),according to procedures known in the arts of organic and medicinalchemistries for the N-substitution of imidiazole derivatives and thepreparations of sulfonamides, thioureas, N-aryl analogs, reductiveamination analogs, and the like described above for Scheme 1.

An alternative to the above method for the preparation of a compound offormula (A) is illustrated in Scheme 13, wherein the imidazole ring issynthesized last Here, an anilino-benzoate of formula (F) isfunctionalized to incorporate the R_(a) group to provide an ester offormula (G). The ester of formula (G) is then hydrolyzed, and theresulting corresponding carboxylic acid is activated with a carboxylicacid activating agent such as for example, N,N′-carbonyldimidazole(CDI), N,N′-dicyclohexylcarbodiimide (DCC), and water solublecarbodiimides, and reacted with a di-amino compound of formula (B) underdehydrating conditions to give the compound of formula (A) wherein R₅ ishydrogen. The compound of formula (A) wherein R₅ is hydrogen can beconverted to a compound of formula (A) wherein R₅ is as defined abovefor a compound of formula (A) according to procedures known in the artsof organic and medicinal chemistries for the N-substitution of imidazolederivatives.

Examples of a diamino compound of formula (B) include:2,3-diaminopyridine, 3,4-diaminopyridine, 4,5-diaminopyrimidine,3,4-diaminopyridazine, 4,5-diaminopyridazine, and 2,3-diaminopyrazine.2,3-diaminopyridine, 3,4-diaminopyridine, and 4,5-diaminopyrimidine arefrom Aldrich Chemicals, Milwaukee, Wis., USA. Other diamino reagents areknown in the literature. For example, 2,3-diaminopyrazine can beobtained according to Sato Nobuhiro; Mizuno, Hajime. Studies ofpyrazines. Part 33. Synthesis of 2,3-diaminopyrazines via[1,2,5]thiadiazolo[3,4-b]pyrazines., J. Chem. Res., Synop.,1997;7:250-251. 4,5-Diaminopyridazine are obtained according toMarcelis, Antonius T. M.; Tondijs, Hanna; Van der Plas, Henk C.Amination of 4-nitro- and 4-cyanopyridazines by liquid ammonia/potassiumpermanganate. J. Heterocycl. Chem., 1988;25(3):831-833 and3,4-diaminopyridazines are obtained according to Klinge D. E.; Van derPlas H. C. NMR studies on σ-adducts of heterocyclic systems withnucleophiles. VII. Proton NMR investigations on σ-adduct formation ofpyridazine, of pyridazine 1-oxide, and some of its derivatives withammonia New substitution mechanism. Recl. Trav. Chim. Pays-Bas,1975;94(11):233-236.

wherein Q₁, Q₂, Q₃, Q₄, R₄, R₅, and R_(a) are as defined above forformula (A).

wherein Q₁, Q₂, Q₃, Q₄, R₄, R₅, and R_(a) are as defined above forformula (A).

The invention also includes disclosed compounds having one or morefunctional groups (e.g., hydroxyl, amino, or carboxyl) which may bemasked by a protecting group so as to avoid unwanted side reactions.Some of these masked or protected compounds are pharmaceuticallyacceptable; others will be useful as intermediates. Protecting groupssuch as for example, those for hydroxy, amino, and carboxy groups arewell-known to those skilled in the art of synthetic organic chemistry.The use of protecting groups is fully described by Greene and Wuts in“Protecting Groups in Organic Synthesis” (John Wiley & Sons Press,2^(nd) ed.). Examples of suitable protecting groups are provided below.

Hydroxyl Protecting Groups

Hydroxyl protecting groups include: ethers, esters, and protection for1,2- and 1,3-diols. The ether protecting groups include: methyl ether,substituted methyl ethers including alkyl, cyclic ethers, and cyclicthioethers, substituted ethyl ethers, benzyl ether, substituted benzylethers, substituted aryl ethers, and silyl ethers. Silyl ethers can beconverted to other functional groups.

Substituted Methyl Ethers

Substituted methyl ethers include: methoxymethyl, methylthiomethyl,t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl,p-ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl,t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, alkyl, benzyl, 2,2,2-trichloroethoxymethyl,bis(2-chloro-ethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-ethanobenzofiran-2-yl.

Substituted Ethyl Ethers

Substituted ethyl ethers include: 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, andt-butyl.

Substituted Benzyl Ethers

Substituted benzyl ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl,p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolylN-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri-(p-methoxyphenyl)methyl,4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)-methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo) anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Substituted Aryl Ethers

Substituted aryl ethers include p-chlorophenyl, p-methoxyphenyl, and2,4-dinitrophenyl.

Silyl Ethers

Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl,dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl,tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, andt-butylmethoxy-phenylsilyl.

Esters

Examples of protective esters of hydroxy groups include: formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,p-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate,4-methoxycrotonate, benzoate, p-phenylbenzoate, and2,4,6-trimethylbenzoate (mesitoate).

Carbonates

Carbonate protecting groups of hydroxy groups include: methyl carbonate,9-fluorenylmethyl carbonate, ethyl carbonate, 2,2,2-trichloroethylcarbonate, 2-(trimethylsilyl) ethyl carbonate, 2-(phenylsulfonyl)ethylcarbonate, 2-(triphenylphosphonio)ethyl carbonate, isobutyl carbonate,vinyl carbonate, alkyl carbonate, p-nitrophenyl carbonate, benzylcarbonate, p-methoxybenzyl carbonate, 3,4dimethoxybenzyl carbonate,o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonatecarbonate, 4-ethoxy-1-naphthyl carbonate, and methyl dithiocarbonate.

Assisted Cleavage

Examples of assisted cleavage protecting groups include: 2-iodobenzoate,4-azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzene-sulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxymethyl)benzoate, and 2-(methylthiomethoxymethyl)benzoate. Assisted cleavage protecting groups are groups that contain asecond, remote functionality that is unreactive towards the primaryfunctionality masking the group being protected, but which can beconverted to a functionality which is reactive towards the primaryfunctionality masking the group being protected such that thedeprotective cleavage reaction of the primary functionality isfacilitated.

Sulfonates

Protective sulfates include: Methanesulfonate (mesylate),benzylsulfonate, and tosylate.

Miscellaneous Protecting Groups

In addition to the above classes, miscellaneous esters include:2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetrarmethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate (tigloate),o-(methoxycarbonyl) benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,sulfate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.

Protection for 1,2- and 1,3-Diols

The protection for 1,2 and 1,3-diols group includes: cyclic acetals andketals, cyclic ortho esters, and silyl derivatives.

Cyclic Acetals and Ketals

Cyclic acetals and ketals include: methylene, ethylidene,1-t-butylethylidene, 1-phenylethylidene, (4methoxyphenyl)ethylidene,2,2,2-trichloroethylidene, acetonide(isopropylidene), cyclopentylidene,cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene,2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and2-nitrobenzylidene.

Cyclic Ortho Esters

Cyclic ortho esters include: methoxymethylene, ethoxymethylene,dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidine,1,2-dimethoxyethylidene, α-methoxybenzylidene,1-(N,N-dimethylamino)ethylidene derivative, α-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

Protection for the Carboxyl Group

Esters

Ester protecting groups include: esters, substituted methyl estersincluding cyclic esters, 2-substituted ethyl esters, benzyl, substitutedbenzyl esters, silyl esters, activated esters, miscellaneousderivatives, alkyl, and stannyl esters.

Substituted Methyl Esters

Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl,methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl,phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N-phthalimidomethyl.

2-Substituted Ethyl Esters

2-Substituted ethyl esters include: 2,2,2-trichloroethyl, 2-bromoethyl,2-chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethyl,1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)-ethyl,2-(p-toluenesulfonyl)ethyl 2-(2′-pyridyl)ethyl,2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl,cyclopentyl, cyclohexyl, 3-buten-1-yl, and4-(trimethylsilyl)-2-buten-1-yl.

Substituted Benzyl Esters

Substituted benzyl esters include: triphenylmethyl, diphenylmethyl,bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl,5-dibenzo-suberyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromylmethyl,2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl,p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl,4-sulfobenzyl, piperonyl, and 4-P-benzyl.

Silyl Esters

Silyl esters include: trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl, anddi-t-butylmethylsilyl.

Miscellaneous Derivatives

Miscellaneous derivatives include: oxazoles, 2-alkyl-1,3-oxazolines,4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, orthoesters, phenyl group, and pentaaminocobalt(III) complex. Aryl estersinclude phenyl and p-(methylmercapto)-phenyl. Other esters includecinnamyl and α-methyl cinnamyl.

Stannyl Esters

Examples of stannyl esters include: triethylstannyl andtri-n-butylstannyl.

Amides and Hydrazides

Amides include: N,N-dimethyl, pyrrolidinyl, piperidinyl,5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl,N-8-nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.Hydrazides include: N-phenyl, N,N′-diisopropyl and other dialkylhydrazides.

Protection for the Amino Group

Carbamates

Carbamates include: carbamates, substituted ethyl including cyclicsubstituted ethyl, assisted cleavage, photolytic cleavage, urea-typederivatives, and miscellaneous carbamates.

Carbamates

Carbamates include: methyl and ethyl, 9-fluorenylmethyl,9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydro-thioxanthyl)]methyl,and 4-methoxyphenacyl.

Substituted Ethyl

Substituted ethyl protective groups include: 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2,-trichloroethyl, 1-methyl-1-(4biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-pyridyl)ethyl,2-(N,N-icyclohexylcarboxamido)-ethyl, t-butyl, and 1-adamantyl.

Miscellaneous groups include: vinyl, alkyl, 1-isopropylalkyl, connamyl,4-nitrocinnamyl, quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl,p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl,2,4-dichlorobenzyl, 4methylsulfinylbenzyl, 9-anthrylmethyl, anddiphenylmethyl.

Assisted Cleavage

Protection via assisted cleavage includes: 2-methylthioethyl,2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and2-(trifluoromethyl)-6-chromonylmethyl. The above definition of assistedcleavage protecting groups is hereby incorporated by reference.

Photolytic Cleavage

Photolytic cleavage methods use groups such as: m-nitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

Urea-Type Derivatives

Examples of urea-type derivatives include: phenothiazinyl-(10)-carbonylderivative, N′-p-toluenesulfonylaminocarbonyl, andN′-phenylaminothiocarbonyl.

Miscellaneous Carbamates

In addition to the above, miscellaneous carbamates include: t-amyl,S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl,cyclopentyl, cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethyl-carboxamido)-benzyl,1,1-dimethyl-3(N,N-dimethylcarboxamido)propyl, 1,1-dimethyl-propynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1(p-henylazophenyl)-ethyl,1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl,p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl,4-(trimethylammonium)benzyl, and 2,4,6-trimethylbenzyl.

Amides

Amides

Amides include: N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,N-3-pyridyl-carboxamide, N-benzoylphenylalanyl derivative, N-benzoyl,and N-p-phenylbenzoyl.

Assisted Cleavage

Assisted cleavage groups include: N-o-nitrophenylacetyl,N-o-nitrophenoxyacetyl, N-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethioninederivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one. The above definition of assisted cleavageprotecting groups is hereby incorporated by reference.

Cyclic Imide Derivatives

Cyclic imide derivatives include: N-phthalimide, N-dithiasuccinoyl,N-2,3-diphenyl-maleoyl, N-2,5-dimethylpyrrolyl,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted3,5-dinitro-4-pyridonyl.

Special —NH Protective Groups

Protective groups for —NH include: N-alkyl and N-aryl amines, iminederivatives, enamine derivatives, and N-heteroatom derivatives (such asN-metal, N—N, N—P, N—Si, and N—S), N-sulfenyl, and N-sulfonyl.

N-Alkyl and N-Aryl Amines

N-alkyl and N-aryl amines include: N-methyl, N-alkyl,N-[2-(trimethylsilyl)ethoxyl]-methyl, N-3-acetoxypropyl,N-(1-isopropyl4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts,N-benzyl, N-di(4methoxyphenyl)methyl, N-5-dibenzosuberyl,N-triphenylmethyl, N-(4methoxyphenyl)diphenylmethyl,N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene,N-ferrocenylmethyl, and N-2-picolylamine N′-oxide.

Imine Derivatives

Imine derivatives include: N-1,1-dimethylthiomethylene, N-benzylidene,N-p-methoxybenzylidene, N-diphenylmethylene,N-[(2-pyridyl)mesityl]methylene, N-(N′,N′,-dimethylaminomethylene),N,N′-isopropylidene, N-p-nitrobenzylidene, N-salicylidene,N-5-chlorosalicylidene, N-(5-chloro-2-hydroxyphenyl)-phenylmethylene,and N-cyclohexylidene.

Enamine Derivative

An example of an enamine derivative isN-(5,5-dimethyl-3-oxo-1-cyclohexenyl).

N-Hetero Atom Derivatives

N-metal derivatives include: N-borane derivatives, N-diphenylborinicacid derivative, N-[phenyl(pentacarbonylchromium- or-tungsten)]carbenyl, and N-copper or N-zinc chelate. Examples of N—Nderivatives include: N-nitro, N-nitroso, and N-oxide. Examples of N—Pderivatives include: N-diphenylphosphinyl, N-dimethylthiophosphinyl,N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl,and N-diphenyl phosphoryl. Examples of N-sulfenyl derivatives include:N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,N-2-nitro-4-methoxy-benzenesulfenyl, N-triphenylmethylsulfenyl, andN-3-nitropyridinesulfenyl. N-sulfonyl derivatives include:N-p-toluenesulfonyl, N-benzenesulfonyl,N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,N-2,4,6-trimethoxybenzenesulfonyl,N-2,6-dimethyl-4-methoxy-benzenesulfonyl, N-pentamethylbenzenesulfonyl,N-2,3,5,6-tetramethyl-4-methoxybenzene-sulfonyl,N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,N-2,6-dimethoxy-4-methylbenzenesulfonyl,N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl,N-β-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl,N-4-(4′,8′-dimethoxynaphthyl-methyl)-benzenesulfonyl, N-benzylsulfonyl,N-trifluoromethylsulfonyl, and N-phenacyl-sulfonyl.

Disclosed compounds which are masked or protected may be prodrugs,compounds metabolized or otherwise transformed in vivo to yield adisclosed compound, e.g., transiently during metabolism. Thistransformation may be a hydrolysis or oxidation which results fromcontact with a bodily fluid such as blood, or the action of acids, orliver, gastrointestinal, or other enzymes.

The invention is further described in the working examples describedbelow. The examples are provided for illustration only, and are not tobe construed as limiting the invention in any respect.

D. EXAMPLES

Examples of the preparation of compounds of the present invention and ofassays useful in characterizing the biological effects of said compoundsare described below.

Chemical Example 1 Synthesis of5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenylamine

Step (a): Synthesis of5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-nitrobenzene

2,3-Diaminopyridine (10 g, 91.6 mmol) and 18.07 g of 4-methoxy-3-nitrobenzoic acid were mixed together, and the mixture was added in portionsto 200 mL of phosphorous oxychloride at. room temperature. The resultingmixture was heated to reflux for 4 hours, and then cooled to roomtemperature and allowed to stir overnight. The reaction was rotaryevaporated in vacuo, and the residue was carefully quenched withsaturated sodium bicarbonate solution, filtered, and dried on the vacuumfilter overnight to give a brown solid. The solid was washed withseveral fractions of ethyl acetate to yield 21.36 g of5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-nitrobenzene as a dark brownsolid that was used without further purification. ¹H-NMR (DMSO-d₆); δ8.71 (d, 1H), 8.48 (dd, 1H), 8.31 (dd, 1H), 7.99 (d, 1H), 7.58 (d, 1H),7.23 (dd, 1H), 4.00 (s, 3H) ppm.

Step (b): Synthesis of5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenylamine

5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-methoxy-nitrobenzene (7.0 g, 26mmol) was dissolved in 200 mL acetic acid, and zinc powder (35 g, 535mmol) was added in portions. The zinc was added at such a rate as tokeep the temperature of the reaction mixture under 40° C. After completeaddition, the reaction mixture was stirred for 3 hours and filtered togive solid. The solids wee washed with water and acetic acid. Thefiltrate was rotary evaporated in vacuo, and the residue was partitionedbetween 1 M NaOH and chloroform. The aqueous layer was extracted severaltimes with chloroform, and the combined organic layers were dried overmagnesium sulfate, filtered, and rotary evaporated to give 0.71 g of5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenylamine as a tan solid.¹H-NMR (CDCl₃): δ 8.06 (dd, 1H), 7.66 (dd, 1H), 7.41 (s, 1H), 7.35 (dd,1H), 6.91 (dd, 1H), 6.64 (d, 1H), 3.67 (s, 3H) ppm. Anal. (C₁₃H₁₂N₄O₁)C,H,N values were within 0.4% of the theoretical values.

Chemical Example 2 Synthesis of Thiophene-2-sulfonic acid[5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenyl]-amide

5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenylamine (0.5 g, 2.1 mmolprepared as described above in Chemical Example 1) was dissolved in 15mL pyridine at room temperature. Solid thiophene 2-sulfonyl chloride(0.38 g, 2.1 mmol) was added and the resulting blood red solution wasstirred overnight The reaction mixture was poured into 250 mL water,stirred for 30 minutes, and filtered to give a pink solid. The solid wasrecrystallized from ethyl acetate after treatment with decolorizingcharcoal to give 0.16 g of thiophene-2-sulfonic acid[5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenyl]-amide as anoff-white solid; mp 252-254° C. ¹H-NMR (DMSO-d₆): δ 13.26 (d, 1H), 9.85(bs, 1H), 8.27 (m, 2H), 8.02 (m, 2H), 7.87 (d, 1H), 7.43 (d, 1H), 7.16(m, 3H), 3.59 (s, 3H) ppm. Anal. (C₁₇H₁₄N₄O₃S₂) C,H,N values were within0.4% of theoretical values.

Biological Example 1 Rabbit Reticulocyte 15-LO Assay (h15LO)

The h15LO assay measures inhibition of 15-LO catalyzed oxidation oflinoleic acid to the hydroperoxy fatty acid 13-(S)HPODE, a conjugateddiene. In the h15LO assay, a test compound is incubated with 15-LOenzyme in the presence of the linoleic acid substrate. For example, 2units (U) of rabbit reticulocyte 15-LO and 174 μM linoleic acid areincubated with a known amount of a test compound for 15 minutes at 4° C.The total reaction volume is 100 μL in phosphate buffered saline (PBS)containing 0.2% sodium cholate. The reaction is stopped with 100 μL ofmobile phase and 10 μL of triethyl phosphite. 13-(S)HPODE is reducedwith triethyl phosphite to the more stable 13-hydroxyoctadecadienoate(13-HODE), which prevents artificial, nonenzymatic lipidperoxidation andproduct breakdown in the sample. 13-HPODE is quantitated by comparingpeak areas of individual samples with those from a standard curvegenerated using authentic 13-HODE. The test reaction is compared to acontrol reaction, which is identical to the test reaction except no testcompound is present. Percent inhibition is calculated as the amount of13-HODE produced in the test reaction divided by the amount of 13-HODEproduced in the control reaction, expressed as a percent.

15-LO is obtained from phenylhydrazine-treated rabbits and purifiedaccording to the method of Rapoport (Rapoport et al., European Journalof Biochemistry, 1979;96:545-561).

Biological Example 2 Monocyte Recruitment

The recruitment or chemotaxis of monocytes is assayed by methodswell-known to those skilled in the art. In particular, the method setforth in J. Clin. Invest., 1988;82:1853-1863, which is herebyincorporated by reference, can be used.

Biological Example 3 Collagen-Induced Arthritis in Mice

Type II collagen-induced arthritis (CIA) in mice is an experimentalmodel of arthritis that has a number of pathologic, immunologic, andgenetic features in common with rheumatoid arthritis. Type II collagen(CII) is a major component of joint cartilage. The disease CIA isinduced by immunization of DBA/1 mice with 100 μg of type II collagendelivered intradermally in Freund's complete adjuvant. Diseasesusceptibility in this model is regulated by the Class II MHC genelocus, which is analogous to the known association of rheumatoidarthritis with the HLA-DR4 gene locus.

A progressive and inflammatory arthritis develops in the majority of theimmunized mice, characterized by paw width increases of up to 100%. Atest compound is administered to mice in a range of amounts, such as 20,60, 100, and 200 mg of test compound per kilogram of body weight perday. The duration of the test can be several weeks to a few months, suchas 40, 60, or 80 days. A clinical scoring index is used to assessdisease progression independently in each paw from Stage 1, erythema andedema (score=1), to Stage 2, joint distortion (score=2), to Stage 3,joint ankylosis (score=3). The disease CIA is variable in that it canaffect one or all paws in an animal, resulting in a total possible scoreof 12 for each mouse. Histopathology of an arthritic joint revealssynovitis, pannus formation, and cartilage and bone erosions. All mousestrains that are susceptible to CIA are high antibody responders to typeII collagen, and exhibit a marked cellular response to CII.

Biological Example 4 SCW-Induced Monoarticular Arthritis

Arthritis is induced as described by Schwab et al., Infection andImmunity, 1991;59:4436-4442, which is hereby incorporated by reference,with minor modifications. Rats receive 6 μg of sonicated streptococcalcell wall (SCW) particles (in 10 μL Dulbecco's PBS [DPBS]) by anintraarticular injection into the right tibiotalar joint on Day 0. OnDay 21, the DTH is initiated with 100 μg of SCW (250 μL) administeredIV. For oral compound studies, compounds are suspended in vehicle (0.5%hydroxypropyl-methylcellulose/0.2% Tween 80), sonicated, andadministered twice daily (10 mL/kg volume) beginning 1 hour prior toreactivation with SCW. Compounds are administered in amounts between 10and 500 mg/kg body weight/day, such as 20, 30, 60, 100, 200, and 300mg/kg/day. Edema measurements are obtained by determining the baselinevolumes of the sensitized hindpaw before reactivation on Day 21, andcomparing them with volumes at subsequent time points such as Day 22,23, 24, and 25. Paw volume is determined by mercury plethysmography.

Biological Example 5 Murine Ovalbumin-Induced Eosinophilia

The murine ovalbumin-induced eosinophilia assay measures the increase ofeosinophil cells in lungs and upper airways in animals administered acompound of the present invention versus control animals administeredonly vehicle. In this assay, female C57BL/6 mice are obtained from theJackson Laboratory (Bar Harbor, Me.). All animals are given food andwater ad libitum. Mice are sensitized with a single IP injection ofovalbumin (OVA) (Grade V, Sigma Chemical Company, St Louis, Mo.)adsorbed to aluminum potassium sulfate (alum), (10 μg OVA+9 mg alum in200 μL saline), or vehicle control (9 mg alum in 200 μL saline) on Day0. On Day 14, the mice are challenged with a 12-minute inhalation of anaerosol consisting of 1.5% OVA (weight/volume) in saline produced by anebulizer (small particle generator, model SPAG-2; ICN Pharmaceuticals,Costa Mesa, Calif.). Groups of eight mice are dosed with oral vehicle(0.5% hydroxypropylmethylcellulose/0.25% polyoxethylene-sorbitanmonooleate [TWEEN-80]), or a test compound at 10, 30, or 100 mg/kg inoral vehicle, 200 μL per mouse PO. Dosing is performed once per daystarting on Day 7 or 13, and extending through Day 16.

For determination of pulmonary eosinophilia, 3 days after the first OVAaerosol challenge (Day 17), the mice are anesthetized with an IPinjection of anesthetic (Ketamine/Acepromazine/Xylazine), and thetracheae is exposed and cannulated. The lungs and upper airways arelavaged twice with 0.5 mL of cold PBS. A portion (200 μL) of thebronchoalveolar lavage (BAL) fluid is enumerated using a Coulter counterModel ZB1 (Coulter Electronics, Hialeah, Fla.). The remaining BAL fluidis then centrifuged at 300×g for 5 minutes, and the cells areresuspended in 1 mL of Hank's Balanced salts (HBSS) (Gibco BRL)containing 0.5% fetal calf serum (HyClone) and 10 mMN-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES) (Gibco BRL).The cell suspension is centrifuged in a cytospin (Shandon SouthernInsments, Sewickley, Pa.) and stained by Diff Quick (American ScientificProducts, McGraw Park, Ill.) to differentiate BAL leukocytes intoneutrophil, eosinophil, monocyte, or lymphocyte subsets. The number ofeosinophils in the BAL fluid is determined by multiplying the percentageof eosinophils by the total cell count.

Biological Example 6 Human Lysate 15-LO Assay (HUM15LO)

The HUM15LO assay measures inhibition of 15-LO catalyzed oxidation oflinoleic acid to the hydroperoxy fatty acid 13-(S)HPODE, a conjugateddiene. In the HUM15LO assay, a test compound was incubated with 15-LOenzyme in the presence of the linoleic acid substrate. For example, aknown amount of a compound of the present invention and 100 μL of human15-LO and 174 μM of linoleic acid in PBS containing 0.2% sodium cholatewere incubated for 15 minutes at 4° C. The test reaction was stoppedwith 100 μL of mobile phase and 10 μL of triethyl phosphite. 13-(S)HPODEwas reduced with triethyl phosphite to the more stable13-hydroxyoctadecadienoate (13-HODE), which prevents artificial,nonenzymatic lipidperoxidation and product breakdown in the sample.13-HPODE was quantitated by comparing peak areas of individual sampleswith those from a standard curve generated using authentic 13-HODE. Thetest reaction was compared to a control reaction, which is identical tothe test reaction except a test compound is not present. Percentinhibition was calculated as the amount of 13-HODE produced in the testreaction divided by the amount of 13-HODE produced in the controlreaction, expressed as a percent.

Human 15-LO was generated in a recombinant 15-lipoxygenase bacculovirusexpression system, using Gibco/BRL/Life Technologies' Bac-to-Bacexpression reagents; T4 DNA ligase, Kanamycin, Gentamicin, tetracycline,penicillin, streptomycin, Bluo-gal, IPTC; DH10Bac competent cells, SOC,LB medium, Sf-900 II SFM media, Sf9 insect cells, Cell Fectin, andEcoRI, BamHI, and KpnI restriction enzymes.

Human Lysate Data for Representative Compounds

5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenylamine (ChemicalExample 1): 39% inhibition at 10 μM; and

Thiophene-2-sulfonic acid[5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenyl]-amide (ChemicalExample 2): IC₅₀=10 μM.

E. Uses

The disclosed compounds of Formula I will be formulated by standardmethods into pharmaceutical compositions that are useful as prophylacticor therapeutic treatments for diseases modulated by the 15-LO cascade.The compositions will be administered to mammals for treating andpreventing inflammation and atherosclerosis.

1. Dosages

Those skilled in the art will be able to determine, according to knownmethods, the appropriate dosage for a patient, taking into accountfactors such as age, weight, general health, the type of pain requiringtreatment, and the presence of other medications. In general, aneffective amount will be between 0.1 and 1000 mg/kg per day, preferablybetween 1 and 300 mg/kg body weight, and daily dosages will be between10 and 5000 mg for an adult subject of normal weight.

2. Formulations

Dosage unit forms include tablets, capsules, pills, powders, granules,aqueous and nonaqueous oral solutions and suspensions, and parenteralsolutions packaged in containers adapted for subdivision into individualdoses. Dosage unit forms can also be adapted for various methods ofadministration, including controlled release formulations, such assubcutaneous implants. Administration methods include oral, rectal,parenteral (intravenous, intramuscular, subcutaneous), intracisternal,intravaginal, intraperitoneal, intravesical, local (drops, powders,ointments, gels, or cream), and by inhalation (a buccal or nasal spray).

Parenteral formulations include pharmaceutically acceptable aqueous ornonaqueous solutions, dispersion, suspensions, emulsions, and sterilepowders for the preparation thereof. Examples of carriers include water,ethanol, polyols (propylene glycol, polyethylene glycol), vegetableoils, and injectable organic esters such as ethyl oleate. Fluidity canbe maintained by the use of a coating such as lecithin, a surfactant, ormaintaining appropriate particle size. Carriers for solid dosage formsinclude (a) fillers or extenders, (b) binders, (c) humectants, (d)disintegrating agents, (e) solution retarders, (f) absorptionaccelerators, (g) adsorbents, (h) lubricants, (i) buffering agents, and(j) propellants.

Compositions may also contain adjuvants such as preserving, wetting,emulsifying, and dispensing agents; antimicrobial agents such asparabens, chlorobutanol, phenol, and sorbic acid; isotonic agents suchas a sugar or sodium chloride; absorption-prolonging agents such asaluminum monostearate and gelatin; and absorption-enhancing agents.

FORMULATION EXAMPLE 1 Tablet Formulation: Ingredient Amount (mg) Thecompound of Chemical Example 1 25 Lactose 50 Cornstarch (for mix) 10Cornstarch (paste) 10 Magnesium stearate (1%) 5 Total 100

The compound of Chemical Example 1, lactose, and cornstarch (for mix)are blended to uniformity. The cornstarch (for paste) is suspended in200 mL of water and heated with stirring to form a paste. The paste isused to granulate the mixed powders. The wet granules are passed througha No. 8 hand screen and dried at 80° C. The dry granules are lubricatedwith the 1% magnesium stearate and pressed into a tablet. Such tabletscan be administered to a human from one to four times a day fortreatment of diseases responsive to the inhibition of the enzyme15-lipoxygenase.

Formulation Example 2

Coated Tablets

The tablets of Formulation Example 1 are coated in a customary mannerwith a coating of sucrose, potato starch, talc, tragacanth, andcolorant.

Formulation Example 3

Injection Vials

The pH of a solution of 500 g of the compound of Chemical Example 2 and5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 L ofdouble-distilled water using 2 M hydrochloric acid. The solution issterile filtered, and the filtrate is filled into injection vials,lyophilized under sterile conditions, and aseptically sealed. Eachinjection vial contains 25 mg of the compound of Chemical Example 2.

Formulation Example 4

Suppositories

A mixture of 25 g of the compound of Chemical Example 1, 100 g of soyalecithin, and 1400 g of cocoa butter is fused, poured into molds, andallowed to cool. Each suppository contains 25 mg of the compound ofChemical Example 1.

Formulation Example 5

Solution

A solution is prepared from 1 g of the compound of Chemical Example 2,9.38 g of NaH₂PO₄.12H₂O, 28.48 g of Na₂HPO₄.12H₂O, and 0.1 gbenzalkonium chloride in 940 mL of double-distilled water. The pH of thesolution is adjusted to pH 6.8 using 2 M hydrochloric acid. The solutionis diluted to 1.0 L with double-distilled water, and sterilized byirradiation. A 25 mL volume of the solution contains 25 mg of thecompound of Chemical Example 2.

Formulation Example 6

Ointment

500 mg of the compound of Chemical Example 1 is mixed with 99.5 g ofpetroleum jelly under aseptic conditions. A 5 g portion of the ointmentcontains 25 mg of the compound of Chemical Example 1.

Formulation Example 7

Capsules

Two kilograms of the compound of Chemical Example 2 are filled into hardgelatin capsules in a customary manner such that each capsule contains25 mg of the invention compound.

Formulation Example 8

Ampoules

A solution of 2.5 kg of the compound of Chemical Example 1 is dissolvedin 60 L of double-distilled water. The solution is sterile filtered, andthe filtrate is filled into ampoules. The ampoules are lyophilized understerile conditions and aseptically sealed. Each ampoule contains 25 mgof the compound of Chemical Example 1.

From the above disclosure and examples, and from the claims below, theessential features of the invention are readily apparent. The scope ofthe invention also encompasses various modifications and adaptationswithin the knowledge of addition or removal of a protecting group, orthe formation of an ester, pharmaceutical salt, hydrate, acid, or amideof a disclosed compound. Publications cited herein are herebyincorporated by reference in their entirety.

Having described the present invention above, various embodiments of theinvention are hereby claimed as follows.

1. A compound of Formula I:

wherein: Q₁, Q₂, Q₃, and Q₄ are independently selected from CX and N,wherein 1 of Q₁, Q₂, Q₃, and Q₄ is N and X is independently selectedfrom H, halo, hydroxy, CF₃, R₁, OR₁, CO₂R₁, NO₂, NH₂, and SR₁, whereinR₁ is H or C₁-C₄ alkyl;

 is a double-bond between Y₁ and Y₂; Y₁ is CH; and Y₂ is C—W—Ar, whereinW is absent (in other words, a covalent bond), O, S, NR₂, SO, SO₂, CO,CHOH, CH₂, NR₂CH₂, CH₂NR₂, NR₂(CO), or (CO)NR₂, wherein R₂ is H or C₁-C₄alkyl, Ar is a phenyl substituted at the 3- and 4-positions relative toW, with R₃ and R₄, respectively, wherein R₃ is selected from NHR_(a),COOH, —COO(C₁-C₆ alkyl), (phenyl)C₁-C₆ alkoxy, —NH(CO)(C₁-C₆ alkyl),nitro, and amino-C₁-C₆ alkyl-, wherein R_(a) is H, C₁-C₄ alkyl, C₃-C₈cycloalkyl, phenyl, or a heterocyclic radical selected from the groupconsisting of: furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl,pyrrolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyridyl, pyrimidyl, triazinyl, pyrazinyl, pyridazinyl, indolyl,pyrazolyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl,piperazinyl, tetrahydrofuryl, pyrrolidinyl, octahydroindolyl,octahydrobenzothiofuranyl, and octahydrobenzofuranyl, benzyl, —CH₂-(aheterocyclic radical selected from the group consisting of: furyl,oxazolyl, isoxazolyl, thienyl, thiazolyl, pyrrolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl,triazinyl, pyrazinyl, pyridazinyl, indolyl, pyrazolyl, quinolyl,isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl,pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, andoctahydrobenzofuranyl, or -M-T, wherein M is sulfonyl, SO₂NR_(b),CONR_(b), CSNR_(b), or CSR_(b), wherein R_(b) is H, C₁-C₄ alkyl, or aheterocyclic radical selected from the group consisting of: furyl,oxazolyl, isoxazolyl, thienyl, thiazolyl, pyrrolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl,triazinyl, pyrazinyl, pyridazinyl, indolyl, pyrazolyl, quinolyl,isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl,pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, andoctahydrobenzofuranyl, and T is C₁-C₁₈ alkyl, phenyl, or a heterocyclicradical selected from the group consisting of: furyl, oxazolyl,isoxazolyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, triazolyl,tetrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, triazinyl,pyrazinyl, pyridazinyl, indolyl, pyrazolyl, quinolyl, isothiazolyl,piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, pyrrolidinyl,octahydroindolyl, octahydrobenzothiofuranyl, and octahydrobenzofuranyl,and R₄ is C₁-C₂ alkoxy, C₁-C₂ thioalkoxy, hydroxy, halo, or C₁-C₄ alkyl;Z is NR₅, wherein R₅ is H, phenyl(C₁-C₄ alkyl)oxycarbonyl, (C₁-C₄ alkyl)oxycarbonyl, (C₃-C₈ cycloalkyl) oxycarbonyl, (C₃-C₈ cycloalkyl)-(C₁-C₄alkyl)oxycarbonyl, or (C₆-C₁₀ aryl)oxycarbonyl; wherein each alkyl,cycloalkyl, phenyl, benzyl, or heterocyclic radical above is optionallysubstituted with between 1 and 3 substituents independently selectedfrom halo, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, C₁-C₄ alkenyl, C₁-C₄ alkynyl,phenyl, hydroxyl, amino, (amino)sulfonyl, N-acetyl, O-acetyl, C₁-C₄thioalkyl, C₁-C₄ alkoxy, COOR₆, wherein R₆ is H or C₁-C₆ alkyl, SO₃Na,SO₃H, SO₂NH₂, cyano, CH₂NH₂, acetyl, di(C₁-C₄ alkyl)amino, and nitro,wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl, or phenylis in turn optionally substituted with between 1 and 3 substituentsindependently selected from halo, C₁-C₂ alkyl, hydroxyl, amino, andnitro; or a pharmaceutically acceptable salt thereof.
 2. A compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Q₄ is N.3. A compound according to claim 1 of Formula II

or a pharmaceutically acceptable salt thereof.
 4. A compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein Q₃ is N.
 5. Acompound according to claim 1 of Formula III

or a pharmaceutically acceptable salt thereof.
 6. A compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein Q₂ is N.
 7. Acompound according to claim 1 of Formula IV

or a pharmaceutically acceptable salt thereof.
 8. A compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein Q₁ is N.
 9. Acompound according to claim 1 of Formula V

or a pharmaceutically acceptable salt thereof.
 10. A compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R_(a) or R_(b)is a heterocyclic radical selected from 3-pyridyl, 3-picolinyl,2-thienyl, 3-thienyl, 8-quinoyl, and imidazolyl.
 11. A compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R_(a) or R_(b)is one of said phenyl, benzyl, alkyl, heterocyclic radical, or a C₃-C₈cycloalkyl substituted with at least one substituent selected from halo,hydroxyl, amino, (amino)sulfonyl, N-acetyl, O-acetyl, C₁-C₄ thioalkyl,C₁-C₄ alkoxy, COOR₆, SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂, acetyl,di(C₁-C₄ alkyl)amino, trifluoromethyl, and nitro and wherein W is acovalent bond.
 12. A compound of claim 11, or a pharmaceuticallyacceptable salt thereof, wherein said substituent is CO₂R₆, N-acetyl,di(C₁-C₄ alkyl)amino, hydroxy, halo, or trifluoromethyl.
 13. A compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R_(a)is a phenyl or benzyl having a substituent in the 3- or 4-position,substituents in the 3- and 5-positions, or substituents in the 3- and4-positions.
 14. A compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R_(a) is C₁-C₄ alkylsulfonyl or C₁₀-C₁₄alkylsulfonyl.
 15. A compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R₄ is methoxy, hydroxy, or thiomethoxy.16. A compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R₄ is methoxy.
 17. A compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R₅ is H.
 18. Acompound of claim 1, or a pharmaceutically acceptable salt thereof,selected from the group consisting of: Thiophene-2-sulfonic acid[2-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-amide;[2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-pyridin-3trifluoromethyl-amine;[2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-pyridin-3trifluoromethyl-phenyl)-amine;3-{[2-Methoxy-5-(1H-pyrrolo[2,3]pyridin-2-yl)-phenylamino]-methyl}-phenol;1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-thiourea;1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[2,3-b]pyridin-2-yl)-phenyl]-thiourea;Thiophene-2-sulfonic acid[2-methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-amide;[2-Methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;[2-Methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine,3-{[2-Methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)-phenylamino]-methyl}-phenol;1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl]-thioureaThiophene-2-sulfonic acid[2-methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl]-amide;[2-Methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl)-pyridin-3-ylmethyl-amine;[2-Methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;3-{[2-Methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)-phenylamino]-methyl}-phenol;1-(3,5-Dichloro-phenyl)-3-[2-methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenyl]-thiourea;Thiophene-2-sulfonic acid2-methoxy-5-(1H-pyrrolo[3,2-b]-pyridin-2-yl)-phenyl]amide;[2Methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenyl]-pyridin-3-ylmethyl-amine;[2-Methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenyl]-(3-trifluoromethyl-phenyl)-amine;and3-{[2-Methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)-phenylamino]-methyl}-phenol.19. A method for treating arthritis, said method comprisingadministering to patient in need of such treatment atherapeutically-effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable carrier, excipient, ordiluent.
 21. A method for treating arthritis, said method comprisingadministering to patient in need of such treatment atherapeutically-effective amount of a compound of claim 10, or apharmaceutically acceptable salt thereof.
 22. A method for treatingarthritis, said method comprising administering to patient in need ofsuch treatment a therapeutically-effective amount of a compound of claim11, or a pharmaceutically acceptable salt thereof.
 23. A method fortreating arthritis, said method comprising administering to patient inneed of such treatment a therapeutically-effective amount of a compoundof claim 14, or a pharmaceutically acceptable salt thereof.
 24. A methodfor treating arthritis, said method comprising administering to patientin need of such treatment a therapeutically-effective amount of acompound of claim 18, or a pharmaceutically acceptable salt thereof.